The interplay of ROS and the PI3K/Akt pathway in autophagy regulation

Abstract

Autophagy causes the breakdown of damaged proteins and organelles to their constituent components. The phosphatidylinositol 3-kinase (PI3K) pathway played an important role in regulating the autophagic response of cells in response to changing reactive oxygen species (ROS) levels. The PI3K α catalytic subunit inhibits autophagy, while its β catalytic subunit promotes autophagy in response to changes in ROS levels. The downstream Akt protein acts against autophagy initiation in response to increases in ROS levels under nutrient-rich conditions. Akt acts by activating a mechanistic target of the rapamycin complex 1 (mTORC1) and by arresting autophagic gene expression. The AMP-activated protein kinase (AMPK) protein counteracts the Akt actions. mTORC1 and mTORC2 inhibit autophagy under moderate ROS levels, but under high ROS levels, mTORC2 can promote cellular senescence via autophagy. Phosphatase and tensin homolog (PTEN) protein are the negative regulators of the PI3K pathway, and it has proautophagic activities. Studies conducted on cells treated with flavonoids and ionizing radiation showed that the moderate increase in ROS levels in the flavonoid-treated groups corresponded with higher PTEN levels and lowered Akt levels leading to a higher occurrence of autophagy. In contrast, higher ROS levels evoked by ionizing radiation caused a lowering of the incidence of autophagy.

Marine Animal-Derived Compounds and Autophagy Modulation in Breast Cancer Cells

“…Their results demonstrated that oyster ceramide down-regulated VEGF, EGF, and PI3K, which control some of the main signalization pathways associated with breast tumor progression, and inhibited the phosphorylation and degradation of Iκb, which blocks NfκB nuclear translocation by masking its nuclear localization sequence [71]. In line with the published data [72][73][74], these molecular events appeared to stimulate autophagy in exposed cells, as revealed by the accumulation of fluorescent autophagosomes and the increase of the beclin-1 protein level. It is noteworthy that CMAEPn was also able to inhibit angiogenesis in vitro and in vivo, thereby resulting in it being a promising tool relevant to counteracting breast tumorigenesis.…”

Anti-cancer effect of betulin and its derivatives, with particular emphasis on the treatment of melanoma

“…The presented results show that the use of betulinic acid induced autophagy in HCC (hepatocellular carcinoma), as evidenced by LC3 (microtubule-associated protein 1A/1B-light chain 3) conversion, baclin-1 accumulation and downregulation of p62/SQSTM1 (ubiquitin-binding protein p62/sequestosome-1). These findings revealed that betulinic acid treatment promoted the death of hepatocellular carcinoma cells, not only by apoptosis, but also by autophagy [41,42].…”

Autophagy Drives Galectin-1 Secretion From Tumor-Associated Macrophages Facilitating Hepatocellular Carcinoma Progression

“…The PI3K signal has recently been linked to regulating autophagy in response to changing ROS levels. PI3K/mTOR signal acts as an autophagy inhibitor under moderate ROS levels but becomes an autophagy promoter in response to high ROS levels ( Kma and Baruah, 2021 ). In addition, the increase of cellular ROS levels triggers the unconventional secretion of antioxidants ( Cruz-Garcia et al, 2020 ).…”